Pregnane 20-cyanohydrins



Patented July 3, 1951 p UNITED STATES PATENT OFFICE PREGNANE 20- GYANOHYDRINS Lewis H. Sarett, Princeton, N. J assignor to Merck & 00., Inc., Rahway, N. J., a corporation of New Jersey No Drawing. Application September-'22, 1948, Serial No. 50,668, which is a division of application Serial No. 778,465, October 7,1947. Divided and this application July 20, 1950, Serial No. 175,021

Claims. (Cl. 260397.4) 1 Y 2 This invention is concerned generally with Forpurposes of this application the configuranovel steroid compounds and with processes for tion represented by the notation 17.(a) -.hyd rox y is preparing them. More particularly, it relates to to be understood to represent .the configuration the .preparation of A -20-cyanopregnene compresent in the naturally-occurring adrenal com.- pounds from the corresponding 20-keto-pregnane 5 pounds. compounds and to the intermediates utilized in The preferred class .of starting materials utis.

preparing the same. lized in practicing the present invention are 20- This application is a division of my co-pending keto-pregnanes which contain free of esterified application Serial No. 50,668, filed September 22, hydroxyl groupings in the molecule, and which 1948, which in turn, is a division of my co-pend- 10 may also contain keto groupings. These preing application Serial No. 778,465, filed October 7, fer ed S a t materials may b epresented by 1947, now Patent No. 2,541,105, which, in turn, is the following generic formula:

a continuation-in-part of my co-pending application Serial No, 773,525, filed September 11, 1947, now Patent No. 2,541,104. The A -20-cyano pregnene compounds herein described can be con- R verted to the corresponding 17(a)hYd10XY-20- 2 keto-pregnane compounds according to the procedure outlined on the following page and described in detail in said co-pending applications. 20

The (a)-hydroxy groupings in the compounds thus obtained, have the same stereochemical configuration as that present in many of the natural- 1y-occurring adrenal hormones. This is of special wherein R1 and Rs are radicals selectedfrom the interest in the preparation of pregnene-4-diolclass which consists of hydroxy radicals, acyloxy 17 (a) ,21-trione-3,11,20 (commonly known as radicalsand hydrogen and R2 is a radical selected Kendalls Compound E), and its 21-acyl derivfrom the class which consists of keto radicals atives. These compounds are important as and hydrogen. adrenal hormones or in therapy requiring adrenal Examples of this preferred class of starting hormone type compounds. They are further usematerials are: 3(a) -hydroxy-11,20-diketo-pregful in the synthesis of similar hormones and nane, -3eacetoxy-11,201diketo-pregnane, B-penzcompounds. oxy-l1,20-diketo-pregnane, 3(a) -hydroxy -1l,20

According to the present invention, 20-keto diketo-2l hydroxyepregnane, 3(a).-hydroxy -11, pregnane compounds are treated with hydrogen 20-.diketo-21-acetoxy-pregnane, 3(a),21 diacetcyanide or one of its salts to produce the .correoxy-l1,20diketoepregnane, and the like.

sponding 20-hydroxy-20-cyano-pregnane com- In carrying out my improved process, I .or.-.- pound. This product is reacted Withadehydrating dinarily react a starting material of the above agent to produce the corresponding A -.gocyanoclass with hydrogen cyanide, or one of its salts,

pregnene, which is then reacted with an oxidizing preferably in solution in a lower aliphatic alcoagent and the intermediate product hydrolyzed hol. When the resulting 0-20 cyanhydrin conto produce the coresponding 17(a) -hydroxy-20- tains free primary or secondary hydroxyl groupketo-pregnane compound. The 17-hydroxy ings, these may be protected, prior to the dehygroup, introduced according to this novel method, dration reaction, by conversion to the correspondis obtained, surprisingly enough, in only one ing acyloxy radicals. This is accomplished by isomeric form, namely the a or natural conreacting said cyanhydrin with an acylating agent,

figuration. such as a lower aliphatic acid anhydride. Al-

These reactions may be chemically represented ternatively, a secondary hydroxyl group may be in the case of 20-keto-pregnane as follows: protected by oxidation to a ketone, since the 0-20- 03, CH3 ON om CH3 =0 l-ON t=o (1) oxidizing HON Dehydrating agent agent (2) Hydrolysis H H H ZO-keto-pregnane zo-hydroxy-m-cyano-pregnane 'A -2O-cyano-pregnene 17-(a)-hydroxy-20-keto-pregnane cyanhydrin grouping is stable to this treatment. It is ordinarily preferred to conduct this oxidaassavse tion reaction utilizing chromic acid as the oxidizing agent.

The dehydration reaction is best'car'ried out by treating the cyanhydrin, after acylation or oxidation of any free hydroxyl groupings which may be present, with a dehydrating agent, such as phosphorus oxychloride. This reaction is ordinarily carried out in solution in a substantially anhydrous organic solvent, such as pyridine. 7

Moreover, the 20-hydroxy-20-cyano-pregnane compounds are stable to oxidizing agents. This unexpected property makes it possible to react 3,20-dihydroxy 20-cyanorpregnane compounds w th oxidizing agents, such as chromic acid, to produce directly the corresponding 3-keto-20-hydroxy-20-cyano-pregnane compound.

' The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given by way of illustration and not of limitation.

Example 1 CH:

as 1T) O (3) HON CH9 or:

&/ :i OH o- HON I HO HO on. 0N

sium cyanide.

extract washed with water. Crystallization then gives approximately 1.5 g. of 3(a),20-dihydroxy- 20-cyano-ll-keto-pregnane (Compound 2).

To a solution of 1.4 g. of 3(a),20-dihydroxy- 20-cyano-1l-keto-pregnane in '70 cc. of acetic acid is added at 16 C. a solution of 0.9 g. of chromic acid in 7 cc. of acetic acid. At the end of one hour, water is added, the crystalline precipitate filtered and recrystallized from ethyl acetate to produce approximately 0.93 g. of 3,11- diketo-20-hydroxy-20-cyano pregnane (Compound 3), dec. 1'70-l80 C.

About 0.60 cc. of phosphorus oxychloride is added to a solution containing 2.0 g. of 3,11- diketo-20-hydroxy-20-cyano pregnane dissolved in 6.7 cc. of pyridine. After standing at room temperature for 24 hours, the solution is poured into water and dilute hydrochloric acid, extracted Grog with benzene and concentrated to dryness. The crystalline residue consists of nitriles which may be separated chromatographically to produce approximately 300 mg. of A 3,11 diketo- 20 cyano pregnene (Compound 4); M. P. 222-223 C.

Examplez CHgOAc 011,0. d n CN on on o o 10) GRADE GHIQAO Pool d-on CN a Pyridine ""Kiom 118085 oizcon A solution of 2.0 g. of -3(a)- hyd1OXy-21'a0t oxy-l1,20-diketo pregnane (Compound 8), which can be'prepared as described by Von Euw, Lardon and Reichstein, Helv.'Chim. Acta 27, 1287 (1944) is treated in a mixture of 25 cc. of alcohol and o 5 thereto. The resulting solution is maintained-at to room temperature and after 3 hours is diluted igf g i i zzgg ggfid 3 f j and e with water. The addition of a large volume of p p1 rfacovere y Water to the alcohol; hydrogen cyanide mixture 10 filtrat1on. Recrystallization of this material precipitates a gun which is extracted with chloror ethyl acetate glves I Substantlauy P form or ethyl acetate. The extract is washed Y 'h Dregnn with water, and evaporated to small volume un- (Compound 20) M. P. 263-265 C;

Example 3 7 CH3 CH3 CN ICE:

i 0H j HON PO01;

Ac0 .aco- A00- (16) (17) (l8) der reduced pressure. The crystalline precipitate About 1.70 g. of 3(a)-acetoxy-11,20-diketo- (1.3 g.) consists of 3(a),20-dihydroxy-20-cyanopregnane (Compound 16) which-can be prepared 21'-aceto'xy-11-keto pregnane (Compound 9) as shown by Von Euw, Lardon and Reichstein-in dec. 175-185 C. Helv. Chim. Acta 27, 821 (1944) is dissolved in 'A solution of 0.60 g. of chromic acid in 1.2 cc. a mixture of 25 cc. of alcohol and 6.4 cc. of acetic of water and 11 cc. of acetic acid is added to a acid and the solution is treated at 0 C. with-6.0 solution containing about 1.2 g. of 3(a) ,20-dihyg. of potassium cyanide. The solution is allowed droxy-20-cyano-2l-acetoxy-ll-keto-pregnane at to warm to room temperature and after three room temperature. After 1 hour, water is added hours is diluted with Water and the material and the product which precipitates, is filtered which precipitates recovered byfiltration. The and recrystallized from ethyl acetate to produce 40 3(a) -acetoxy-20-'hydroxy 20 -'cy'ano 11 -keto- 3,1l-diketo-20-hydroxy-20-cyano 21 acetoxypregnane (Compound 1'7),thus'obtain'ed maybe pregnan'e (Compound 10); dec. 214-217" C. purified by recrystallization from ethyl acetate. 0.40 cc. of phosphorus-oxychloride is added to It de'composesat about 221-223 C. Yield apa solution containing about 950 mg. of 3,11-diproximately 901%0f theory. keto-20-hydroxy-20-cyano-2 1-acetoxypregnane To a solution of 293mg. of 3(a)-a'cetoxy-20-' dissolved in 3 cc. of pyridine. After standing at hydroxy-20-cyano-"1I-keto-pregnane in 1.000. of room temperature for '24 hours, the solution is dry pyridine is added 0.10 cc. of phosphorus oxypoured into water and dilute hydrochloric acid, chloride. After standing at room temperature extracted with benzene and concentrated to dryfor 24 hours, the solutionis poured into water mess. The crude product, after chromatography and dilutehydrochloric' acid, extracted with bengives one main constituent, namely A -3,11- zene and the benzene extract concentrated to diketo-20-cyano -21 -acetoxy-pregnene (Comdryness. The crystalline residue consists of a pound 11); M. P. 189-190 0'. mixture of unsaturated nitriles which may be This compound is further identified by hydrolyseparated chromatographically to produce A17- sis to the corresponding 21-hydroxy derivative, 3(a)-acetoxy-1l-keto-ZO-cyano-pregnene (Comwithout affecting the cyano grouping. About pound 18) M. P. 194-195 C.

Example 4 omoae CHZOAC CHaOAc I-=0 =0 C-CN i i OH 0=f\ O: 0:?

Acetic HCN anhydride OH Pyndme A00 A00 01310.10 OHQOH LON CN 6 mg. of the A -3,11-diketo-20=cyano'-21-acetoxypregnene (Compound 11) is "dissolvedin'5 cc. of methanol, and a solution containing 200 mg. of potassium carbonate in 2 "cc. of waiter added I (1) P 0 Cl: (2) X011 CHgOH Acetic anhydrlde Pyridine "300 hydroxy-1li20-diketo-z'l acetoxy -pregnane (Compound 22) is treated with excess pyridine-acetic anhydride and the mixture warmed on the steam bath for approximately 10 minutes. The resulting solution is diluted with water and extracted with ether. The ethereal extract, is Washedwith dilute hydrochloric acid, dilute sodium carbonate, and finally with water. The. ether extract is then evaporated to small volume, and petroleum ether is added thereto to produce crystals of 3(a),21-diacetoxy-11,20 diketo-pregnane (Compound 23); M. P. 100-1l0 C., which contain 10% of solvent of crystallization. Recrystallization of this material from benzene-petroleumether gives a product having a dec. point of 82-90 C.

About 3.0 g. of said 3(a),21-di2t06t0XY-11,20- diketo-pregnane is dissolved in a mixture of 30 cc. of alcohol and 11.4 cc. of acetic acid, and the resulting solution is cooled to C. and treated with about 10.6 g. of potassium cyanide. mixture is stirred for about one-half hour, and then permitted to warm to room temperature. After two hours, the solution is diluted with water, and the crystalline precipitate thus obtained is filtered'and washed. The wet cake is dissolved in ethyl acetate, excess water removed and the solution is evaporated to small volume in vacuo. Petroleum ether is added to the resulting solution thereby precipitating crystalline 3 (a) ,21-diacet0xyll -'keto-.20-hydr0xy-20-cyanopregnane (Compound 24); M. P. l48-160 C. with dec. I

To a solution of about 2.2 g. of 3(a),2l-diacetoxy-l1-keto-20-hydroxy-20-cyano-pregnane in about 8 cc. of dry pyridine is added approximately 1.2 cc. of phosphorus. oxychloride. After standing at room temperature for 24 hours, the reaction solution 'is poured into water and'dilute hydrochloric acid. The resulting aqueous mixture is extracted with benzene and the benzene extract is evaporated to produce approximately 2.0 g. of an oil. This oil is subjected to chromatographic separation and the portions which are eluted, employing etroleum ether-ether mixtures, are combined to produce approximately The * a. 3(a),2l-diacetoxy- 11 keto-20-hydroxyQ20-f 1.84 g. "of crude A -3(a) ,21-diacetoxy-lI kto-20- cyano-pregnene which is obtained as an oil. I

This oil is saponified by dissolving in a mixture of 10 'cc. of benzene and 10 cc. of 1.1 N metha-:

nolic potassium hydroxide. After 10 minutes the solution is acidified with'acetio acid, the benzene is evaporated in vacuo, and the residual material crystallized from dilute methanol to produce 1.45 g.'of crude product; M. P. 242-254 C. This material is further purified by recrystallization from acetone and from dilute alcohol to produce substantially pure A -3(a) ,2l-dihydroxy-ll-keto- 20-cyano-pregnene (Compound 25); M. P. 256- 257 C.

This product is treated with excess acetic anhydride and pyridine, at room temperature, to produce substantially pure A -3(a) ,21-diacetoxy- 1l-keto-20-cyano-pregnene (Compound 26).

Various changes and modifications may be made in my invention as described without departing from'the spirit and scope thereof. To the extent that these changes and modifications are within the purview of the annexed claims,

" they are to be considered as part of my inveni l. Pregnane compounds having both a cyano and a hydroxy substituent attached to the C520 carbon atom.

.2. 3(a) -acetoxy-20-hydroxy-20-cyano-1l-ketopregnane,

cyano-pregnane.

J 4. 3-h droxy-ll-keto- 20 hydroxy-20-cyano 21-acetoxy-pregnane.

. 5. 3,11-diketo-20-hydroxy 20 cyano-2l-a t; Q r enane. 7 r a H REFERENCES CITED 0 The following references are of record in the:

' file of this patent:

UNITED STATES PATENTS Number Name Date 2,143,453 Ruzicka Jan. 10, 193.9 2,150,885 schoeller Mar. 14 1939' fLEWis H. SARET'I. 

1. PREGNANE COMPOUNDS HAVING BOTH A CYANO AND A HYDROXY SUBSTITUTED ATTACHED TO THE C-20 CARBON ATOM. 